Our overall goal is to determine the role of hormones and growth factors in the regulation of different phenotypes and oncogene activations in mouse mammary carcinogenesis. One out of nine women in the USA is likely to develop breast cancer during her lifetime. The etiology of breast cancer in women has not been defined. Epidemiological studies indicate that hormones are essential for the growth and differentiation of the breast as well as the development of breast cancer. Hormone related factors such as early age of menarche, late menopause, full term pregnancy at an early age, are associated with and increase or decrease in risk for breast cancer. Breast cancer is characterized as being heterogeneous in morphology, karyotypes, metastatic capabilities, hormone independence or hormone dependence and response to therapy. Taken together these characteristics provide circumstantial evidence that breast cancer must progress by a variety of pathways. The factors involved in the modulation of these cancer pathways have not been defined. We have developed a defined culture system in which the specific hormones present around the time of carcinogen exposure affect the incidence and type of mammary transformants as well as the molecular events that are associated with mammary carcinogenesis. Our working hypothesis is that the initiation of carcinogenesis is modulated by the mitogenic environment around the time of carcinogen treatment. We propose to study the role of hormones and growth factors in our defined culture system on the regulation of the phenotype and oncogene activation in mammary carcinogenesis. We will study the role of hormones and growth factors in regulating the expression of proto-oncogenes, the repair of DNA adducts, their role in selection of transformants, and the interaction of hormones and growth factors in carcinogenesis. Additionally we have cloned a novel transforming gene that is potentially another molecular probe for the analysis of sequential changes in carcinogenesis. Extensive molecular and biological characterization of the gene will be carried out.